2-219207759-C-T

Variant names:

• chr2-219207759-C-T
• rs1299534586
• NM_138802.3:c.262C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138802.3(ZFAND2B):​c.262C>T​(p.Pro88Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZFAND2B NM_138802.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31

Genes affected

ZFAND2B (HGNC:25206): (zinc finger AN1-type containing 2B) This gene encodes a protein containing AN1-type zinc-fingers and ubiquitin-interacting motifs. The encoded protein likely associates with the proteosome to stimulate the degradation of toxic or misfolded proteins. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFAND2B	NM_138802.3	c.262C>T	p.Pro88Ser	missense_variant	Exon 3 of 9	ENST00000289528.10	NP_620157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFAND2B	ENST00000289528.10	c.262C>T	p.Pro88Ser	missense_variant	Exon 3 of 9	1	NM_138802.3	ENSP00000289528.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.262C>T (p.P88S) alteration is located in exon 3 (coding exon 3) of the ZFAND2B gene. This alteration results from a C to T substitution at nucleotide position 262, causing the proline (P) at amino acid position 88 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.087	.;T;.;T;T;T;T;T;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;D;D;.;D;.;D;.;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	2.9	M;M;M;M;.;.;.;M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0040	D;D;D;D;D;T;D;D;D;T
Sift4G	Uncertain	0.049	D;T;D;T;D;D;D;T;T;D
Polyphen		0.27, 0.78	.;B;.;B;.;.;P;B;.;.
Vest4		0.67
MutPred		0.20		Gain of phosphorylation at P88 (P = 0.023);Gain of phosphorylation at P88 (P = 0.023);Gain of phosphorylation at P88 (P = 0.023);Gain of phosphorylation at P88 (P = 0.023);Gain of phosphorylation at P88 (P = 0.023);Gain of phosphorylation at P88 (P = 0.023);Gain of phosphorylation at P88 (P = 0.023);Gain of phosphorylation at P88 (P = 0.023);Gain of phosphorylation at P88 (P = 0.023);Gain of phosphorylation at P88 (P = 0.023);
MVP		0.59
MPC		0.56
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.50
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1299534586; hg19: chr2-220072481;